With the introduction of glutaraldehyde preservation of biological tissue, and in particular, porcine bioprosthetic heart valves, it has been possible to: (a) overcome the poor performance of early formaldehyde-preserved implanted tissue valves; (b) discontinue the use of homograft valves; and (c) avoid the undesirable use of anticoagulants required to prevent thromboembolism associated with the use of non-bioprosthetic (mechanical) heart valves especially in children. Although the relatively biologically inert glutaraldehyde-preserved valves of Carpentier and others have demonstrated excellent long-term durability in most instances, serious drawbacks such as tissue-fatigue and a propensity toward calcification have plagued their continued use. Moreover, it was initially contemplated that children and adolescents would be among those deriving the greatest benefit from the glutaraldehyde-preserved bioprosthetic heart valves since the anticoagulants required with mechanical prostheses could be eliminated. Results from an increasing number of recent clinical studies, however, indicate that severe calcification of these tissues with relatively short-term failure is prevalent among children and adolescents. Thus, despite their long-term durability and overall reduced incidence of complications, these glutaraldehyde-preserved valves have been deemed by some to be unsuitable for use in children.
Calcification of tissue remains a mystery for the most part; however, various factors including calcium metabolism diseases, age, diet, degeneration of tissue components such as collagen, and turbulance have previously been shown to be involved to a certain extent. Recently, the occurrence of a specific calcium-binding amino acid, laid down after implantation of glutaraldehyde-preserved porcine xenografts, has been demonstrated; and it has been postulated to play a role in calcification. While calcification has been accompanied by degradative changes in the glutaralde-hydetreated collagen fibers of the implanted tissue, it remains unclear whether the dystrophic calcification is a cause or the result of tissue degradation. Nevertheless, there has been a continued effort to elucidate the source of the calcification problem with implanted tissue, with the hope that a remedy will be soon to follow.
One method of inhibiting the intrinsic calcification of biological tissues is to incorporate a polymer into the implantable tissue, as described in U.S. Pat. No. 4,481,009, herein incorporated by reference. One embodiment of this method involves covalently bonding to the tissue a monomer capable of further polymerization. This tissue is then contacted with a second monomer under polymerization conditions such that a tissue-bonded polymer is formed in situ.
While this method of mitigating calcification is suitable for certain applications, not all polymers impart an elastomeric property to the tissue. Such an elastomeric property may be desirable in tissues which will be subjected to stretching or flexing once implanted. Tissues which will be repeatedly stretched or flexed after implantation include, among others, those implanted to form part or all of a diaphragm, heart valve, other portions of an artificial heart, or a bladder. It has been found that when certain relatively non-elastomeric polymers are bound to biological tissue that is subsequently subjected to repeated flexing, the polymer's ability to mitigate calcification of the tissue may be lost. For example, tissue into which a relatively non-elastomeric polymer was incorporated according to the method of U.S. Pat. No. 4,481,009, in which the first monomer solution comprised acrylic acid, and the only monomer in the second monomer solution was acrylamide, became calcified after being subjected to mechanical flexing and then implanted. The non-elastomeric polymer was found to have cracked when repeatedly flexed. Thus, there exists a need for a method of treating implantable biological tissue to inhibit calcification so that the inhibition of calcification is retained in tissues subjected to flexing, stretching, and similar movement after implantation.